The central hypothesis of this proposal is that H1 and 15C MRS can predict and detect response to radiation therapy. The long term goal is to develop in magnetic resonance spectroscopy (MRS) methods for the clinical management of radiation therapy and for experimental cancer research. Availability of such methods would facilitate optimization of radiation treatment schedules to the needs of the individual patient. Sophisticated 1H and 13C MRS methods developed during the previous funding period will be used to test this hypothesis on two well defined tumor models - RIF-l and EMT6 - which have significantly different hypoxic fractions. The ability of these methods to predict radiosensitivity and to detect tumor response to radiation therapy will be evaluated. The mechanisms underlying spectral changes during untreated growth and following radiation therapy will be investigated in perfused cells. Diffusion spectroscopy will be employed to measure changes in intracellular volumes, cellular concentrations of metabolites and transmembrane distribution of key metabolites such as lactate, in a perfused cell system, following irradiation. In viva magnetic resonance measurements will be related to tumor histology radiosensitivity, tumor perfusion and oxygenation. Studies during the previous funding period have already demonstrated that 1H MRS methods with imaging resolution as low as 2 ul at 4.7 T can detect tumor response to radiation doses as low as 2 Gy, the dose employed in clinical fractionated therapy schedules Response to radiation results in a significant decrease in lactate concentration. We have also found that the( rale of glycolysis of RIF-l (a radiation responsive tumor) is about twice that of EMT6 (a radiation resistan tumor) for volume matched tumors. The possibility that glycolytic rate is predictive for solid tumor radiosensitivity for different tumor cell lines and steady state lactate concentration is predictive within a cell line will be examined.